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Transl Oncol. 2019 May;12(5):764-774. doi: 10.1016/j.tranon.2019.02.014. Epub 2019 Mar 17.

Chemotherapy Modulates Endocrine Therapy-Related Resistance Mutations in Metastatic Breast Cancer.

Author information

1
The Affiliated Cancer Hospital of Xiangya Medical School, Central South University / Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, the Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha 410013, China.
2
The Affiliated Cancer Hospital of Xiangya Medical School, Central South University / Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, the Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha 410013, China. Electronic address: oyqc1969@126.com.
3
Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, 33022, USA.
4
Geneplus Beijing Institute, Beijing 102206, China.
5
The Affiliated Cancer Hospital of Xiangya Medical School, Central South University / Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, the Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha 410013, China. Electronic address: huzheyu@hnszlyy.com.

Abstract

PURPOSE:

Accumulation of PIK3CA, ESR1, and GATA3 mutations results in resistance to endocrine therapy in breast cancer patients; however, the response of these genes to chemotherapy is unclear. Therefore, we sought to evaluate the genetic response of circulating tumor DNA (ctDNA) to chemotherapy in metastatic breast cancer patients.

METHODS:

The mutation frequency of 1021 genes was examined prior to chemotherapy in ctDNA of 44 estrogen receptor-positive metastatic breast cancer patients. These genes were evaluated again in a subset of patients (n=24) following chemotherapy. Mutation frequency was defined as the percentage of mutations found in ctDNA compared to total cell-free DNA.

RESULTS:

Prior to chemotherapy, PIK3CA was the most commonly mutated gene, with mutation found in 22 of the metastatic breast cancer patients. Following chemotherapy, 16 patients exhibited progressive disease (PD), and 8 patients experienced no progression (non-PD). PIK3CA mutation frequency increased in 56.25% (9/16) of the PD patients but decreased in 62.5% (5/8) of the non-PD patients. As a result, more PD patients exhibited increased PIK3CA mutation frequency than non-PD patients (56.25% vs 0%, P=.002). Further, ESR1 and GATA3 mutations correlated with PIK3CA mutation. Interestingly, patients receiving the mTOR inhibitor everolimus exhibited a lower progression rate (0% vs 62.5%, P=.001), and the combination of everolimus and chemotherapy effectively suppressed PIK3CA, ESR1, and GATA3 gene mutations.

CONCLUSION:

Together, these results suggest that mTOR inhibition may be a useful chemotherapy adjuvant to suppress chemotherapy-induced gene mutations that render tumors resistant to endocrine therapy in metastatic breast cancer patients with PD.

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